For many years, the central nervous system (CNS) was considered an immune-privileged organ. However, crosstalk between the brain and systemic responses is now increasingly suspected of playing critical roles in CNS disease. This may be especially important in stroke, where infiltration of inflammatory blood cells takes place after cerebral ischemia or hemorrhage. In particular, monocytes/macrophages (M-theta) are thought to worsen brain injury. In this K99 application, we propose the new idea that M-theta cells are not always damaging. Instead, depending on timing and phenotype, these cells can also induce beneficial neurovascular remodeling. Thus, understanding the mechanisms involved may allow us to control M-theta phenotype for promoting brain repair and stroke recovery. To test our hypothesis, we will a multi-disciplinary approach, combining molecular and cell biology with in vivo pharmacology in transgenic mice together with novel biomaterials and in vivo optical imaging. Our ultimate goal is to define a new mechanism for enhancing "brain remodeling" by controlling the beneficial phenotype of M-theta cells. Our pilot data are intriguing: (i) M-theta cells release IL-1B after HMGB1 (DAMP) stimulation, and IL-1B enhances CD200 expression in reactive astrocytes, (ii) CD200 may induce monocyte phenotype into CD34+/Flk1+ cells and change M? phenotype from toll-like receptor 4 (TLR4)high /Flk1low M-theta to TLR4low/Flk1high M- theta after LPS stimulation, (iii) CD34+/Flk1+ cells differentiated from monocytes may induce angiogenesis and growing immature neuron in an in vitro, (iv) early treatment with CD200Fc may increase CD34+/Flk1+ cells and TLR4low/Flk1high M-theta in parallel with reducing massive gliosis and improving neuronal plasticity in peri-infarct cortex after cerebral ischemia in mice. We will build on our pilot data to define a mechanism of crosstalk between the brain reactive astrocyte and systemic circulating monocyte lineage cells. Our hypothesis is two-fold: (1) Astrocytic CD200 switches the monocyte/M-theta phenotype from harmful to beneficial. (2) Regulating CD200-CD200R signaling pathway may lead to new therapeutic approaches to promote "brain remodeling" via "systemic modulation" after a broad range of CNS diseases. I already have published experience in the cell culture and in vivo models. I will learn the biomaterials and in vivo optical imaging tools from my mentor/consultants. My long term goal is to grow and build my independent lab based on the theme of manipulating inflammation for brain repair.
For many years, central nervous system was considered an immune-privileged organ. However, crosstalk between the brain and systemic responses is now increasingly suspected of playing critical roles in stroke. Monocyte/Macrophage (M?) are traditionally thought to contribute to ischemic damages. But emerging data now suggest that these cells can induce beneficial effects dependent on the phenotype. Thus, understanding mechanism how to control the phenotype is quite important to promote neurovascular remodeling. Regulating CD200-CD200R signaling pathway may lead to new therapeutic approaches to promote brain remodeling via systemic monocyte/M? modulation after ischemic or hemorrhagic stroke.
|Hayakawa, Kazuhide; Pham, Loc-Duyen D; Arai, Ken et al. (2014) Reactive astrocytes promote adhesive interactions between brain endothelium and endothelial progenitor cells via HMGB1 and beta-2 integrin signaling. Stem Cell Res 12:531-8|